As noted above, in response to the concern about the appropriate diagnosis for children with chronic, severe irritability, we defined a group of children whom we described as having severe mood dysregulation (SMD). These children have extremely severe irritability and symptoms of hyperarousal (the latter being similar to those seen in attention deficit hyperactivity disorder (ADHD)) and, although they frequently receive the diagnosis of bipolar disorder (BD), they do not indeed meet diagnostic criteria for BD. Our SMD phenotype formed the basis for the new pediatric diagnosis of mood dysregulation disorder with dysphoria (DMDD) in DSM-5. (DMDD differs from SMD primarily in that DMDD does not require the hyperarousal symptoms, related to attention deficit hyperactivity disorder (ADHD)). Since the inception of this project, approximately 220 youth with SMD/DMDD have been recruited into the project. Approximately 20 new patients were recruited this year. It is very important to note that these youth with SMD suffer very severe psychiatric impairment, and indeed are as ill as are youth with BD in terms of number of medications prescribed, number of psychiatric hospitalizations, and standardized measures of function. Also as noted above, in previous years we demonstrated differences between youth with SMD and those with BD in terms of clinical course, family history, and the brain mechanisms associated with behavioral problems. Thus, while we continue to compare youth with BD and those with severe irritability in terms of mediating brain mechanisms, we have become increasingly interested in the pathophysiology of irritability in its own right. Indeed, irritability is one of the most common presenting symptoms in pediatric psychiatry clinics. As noted above, the construct of irritability is particularly well-suited for a transdiagnostic, translational approach consistent with the Research Domain Criteria (RDoC) approach. Therefore, much of our work this year involves examining irritability, not only within the severely irritable DMDD phenotype, but also in other groups that exhibit considerable irritability, including youth with anxiety disorders, ADHD, or bipolar disorder (BD). Across all groups, we characterize irritability as a continuous variable. A major focus of our neuroimaging work includes the use of frustrating tasks, since a hallmark of irritability is difficulty tolerating frustration. In work published last year, we demonstrated behavioral and neural differences between irritable and non-irritable youth while completing a frustrating attentional task. We have improved that paradigm and are now applying it in a large sample of youth with DMDD, BD, ADHD, and/or anxiety disorders, as well as healthy youth. This approach allows us to examine the neural correlates of irritability, operationalized dimensionally, while also comparing DSM-5 diagnostic groups in terms of the brain circuitry engaged during a frustrating task. Preliminary data (N=70 across groups) indicate that increased irritability is associated with increased amygdala-parietal functional connectivity during frustrating, vs. non-frustrating, feedback. This may potentially provide an explanatory mechanism for the attentional dysfunction in irritable children during frustration. A major focus of our work continues to be treatment. We have continued our double-blind trial designed to ascertain whether citalopram (a serotonergic reuptake inhibitor (SRI) antidepressant that is effective in the treatment of pediatric anxiety) plus stimulant is more effective than placebo plus stimulant in the treatment of severe irritability in youth. Importantly, stimulant and SRI treatment tend to be less toxic than the atypical antipsychotic treatment that is considered first-line treatment for bipolar disorder, yet stimulants and SRI's are relatively contraindicated in patients with bipolar disorder because of concern about possibly inducing a manic episode. Therefore, this treatment trial has considerable public health importance. Thus far, we have randomized approximately 45 children into the trial, and youth are tolerating the experimental treatment well. In addition, we are assisting collaborators at UCLA on a similar trial that is funded extramurally. We are also now extending our treatment work to include an adjunctive trial of computer-based training designed to shift subject's perception of faces from angry toward happy. This work is based on our prior work demonstrating face emotion labeling deficits in youth with SMD, and work by our collaborators (Dr. Marcus Munafo at the University of Bristol and Dr. Yair Bar-Haim at Tel Aviv University) that such face labeling training can be associated with decreases in trait anger and irritability. The first step in this work is to demonstrate that we can use implicit face emotion identification training to shift adolescents categorization of angry vs. happy faces. We have trained approximately 20 healthy adolescents, using active vs. sham training, and preliminary data indicate that such shifting does occur with active treatment only. We are now beginning an open pilot trial of such training in irritable children to test a) whether training is successful in this population and b) whether it is associated with decreased irritability. We will also scan the irritable youth pre and post training, using an implicit face emotion identification task, to obtain pilot data as to whether the training alters brain circuitry while processing emotional faces.